The study of regulatory and accessory proteins and virus encoded enzymes of complex retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) and have provided fundamental knowledge to define mechanisms of viral-induced transformation and basic paradigms of cell biology. This Program Project Grant (PPG) application is focused on using retrovirus models to elucidate basic cellular mechanisms governing transcriptional regulation of lymphocytes. This understanding will lead to new insights into the interface between pathogenic mechanisms of the virus during its replication and therapeutic modalities against retroviral-induced cancer. Each project will significantly expand ongoing collaborative efforts between the PPG laboratories. Project #1 is seeking to understand the essential role of p12I and p30II in transcriptional regulation in T-lymphocytes and in the establishment of HTLV-1 infection in vivo. Project #2 will extend the fundamental knowledge that defines the role of phosphorylation in HTLV Rex and thereby learn how this viral protein can be used to study mRNA transport in T-lymphocytes. Project #3 will test post-transcriptional control of retrovirus cell interaction through the use of novel control elements and retroviral vectors. Project #4 defines the role and regulation of parathyroid hormone related protein in ATL and its associated paraneoplastic syndrome, humoral hypercalcemia of malignancy in human and animal models. Project #5 continues the productive collaboration between The Ohio State University and Washington University, St. Louis to determine the role of the regulatory protein Tax in lymphocyte proliferation and virus-associated disease. Three interactive cores support the PPG: Administration/Biostatistics, Imaging, and Animal Models. The overall goal of the PPG is to use retrovirus models to define important mechanisms that determine lymphocyte proliferation and associated disease, as well as to test innovative modalities to ablate the effects of retroviral carcinogenesis.